The present invention relates to novel intermediates for the hemisynthesis of taxanes and to their processes of preparation.
Taxanes, natural substances with a diterpene skeleton which is generally esterified by a xcex2-amino acid side chain derived from N-alkyl- or N-aroylphenylisoserine, are known as anticancer agents. Several dozen taxanes have been isolated from Taxaceae of the genus Taxus, such as, for example, paclitaxel (R1=Ac, R2=Ph, R3xe2x95x90R4=H), cephalomanine, their derivatives deacetylated in the 10 position, or baccatins (derivatives without side chain) represented by the formulae 1 and 2 below. 
To avoid rapidly exhausting its original source, Taxus brevifolia, French researchers have sought to isolate paclitaxel from renewable parts (leaves) of T. baccata, the European yew. They have thus demonstrated the probable biogenetic precursor of taxanes, 10-deacetylbaccatin III, the springboard of choice for the hemisynthesis because of its relative abundance in leaf extracts.
The hemisynthesis of taxanes, such as paclitaxel or docetaxel (R1=Ac, R2=t-butyloxy, R3xe2x95x90R4=H), thus consists in esterifying the 13-hydroxyl of a protected derivative of baccatin or of 10-deacetylbaccatin III with a xcex2-amino acid derivative.
Various processes for the hemisynthesis of paclitaxel or of docetaxel are described in the state of the art (EP-0 253 738, EP-0 336 840, EP-0 336 841, EP-0 495 718, WO 92/09589, WO 94/07877, WO 94/07878, WO 94107879, WO 94/10169, WO 94/12482, EP-0 400 971, EP-0 428 376, WO 94/14787). Two recent works, I. Georg, T. T. Chen, I. Ojima, and D. M. Vyas, xe2x80x9cTaxane Anticancer Agents, Basic Science and Current Statusxe2x80x9d, ACS Symposium Series 583, Washington (1995) and Matthew Suffness, xe2x80x9cTaxol(copyright) Science and Applicationsxe2x80x9d CRC Press (1995), 1500 references cited, comprise exhaustive compilations of hemisyntheses of taxanes.
The xcex2-amino acid side chains derived from N-alkyl- or N-aroylphenylisoserine of paclitaxel or docetaxel are of (2R,3S) configuration and one of the main difficulties in the hemisynthesis of taxanes is to obtain an enantiomerically pure product. The first problem consists in obtaining a pure enantiomer of the phenylisoserine derivatives employed in the hemisynthesis of taxanes. The second problem consists in retaining this enantiomeric purity during the esterification of the baccatin derivative and the subsequent treatments of the products obtained including deprotection of the hydroxyls and similar treatments.
Many studies on asymmetric synthesis involving derivatives of xcex2-amino acids have focused on the chemistry of isoserine and of its derivatives, xcex2-amino acids for which a dehydrated cyclic form is a xcex2-lactam (EP-0 525 589). The majority of the various syntheses of phenylisoserine derivatives useful as precursors of taxane side chains focus on a common intermediate, (2R,3R)-cis-xcex2-phenylglycidic acid, which is subsequently converted to xcex2-phenylisoserine by reaction with ammonia (EP-0 495 718) or a nucleophile (Gou et al., J. Org. Chem., 1983, 58, 1287-89). These various processes require a large number of stages in order to produce xcex2-phenylisoserine of (2R,3S) configuration, necessarily with a stage of racemic resolution by conventional selective crystallization techniques, either for cis-xcex2-phenylglycidic acid or for xcex2-phenylisoserine, or subsequently, after conversion. Furthermore, in order to retain the enantiomeric purity of taxane side chain precursors during the esterification of the baccatin derivative, various means have been provided, in particular by using cyclic intermediates of blocked configuration, which remove the risks of isomerization during esterification reactions under severe reaction conditions. In particular, they involve xcex2-lactam (EP-0 400 971), oxazolidine (WO 92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169, WO 94/12482), oxazinone (EP-0 428 376) or oxazoline (WO 94/14787) derivatives. These cyclic precursors are prepared from the corresponding xcex2-phenylisoserine derivative. As for the latter, the processes provided involve a large number of stages and a necessary racemic resolution in order to obtain the desired taxane side chain precursor. It was thus important to develop a novel route for the improved synthesis of intermediates which are taxane side chain precursors, in particular of enantiomers of cis-xcex2-phenylglycidic acid, of xcex2-phenylisoserine and of their cyclic derivatives.
Finally, for the hemisynthesis of taxanes and in particular of paclitaxel, the sole appropriate baccatin derivative used until now is that for which the 7-hydroxy radical is protected by a trialkylsilyl (EP-0 336 840, WO 94/14787), the deprotection of which is carried out exclusively in acidic medium. It was thus also important to employ novel protective groups for the hydroxyl functional group which in particular make possible selective protection of the 7-hydroxy radical and in addition allow a wider choice of operating conditions for the deprotection stage.
The present invention relates first of all to an improved process for the preparation of taxane side chain precursors.
The process according to the invention comprises converting a cis-xcex2-arylglycidate derivative of general formula I 
in which
Ar represents an aryl, in particular phenyl, and
R represents a hydrocarbon radical, preferably a linear or branched alkyl or a cycloalkyl optionally substituted by one or more alkyl groups;
wherein said process is carried out so as to regio- and stereospecifically introduce the xcex2-N-alkylamide and the xcex1-hydroxyl or their cyclic precursors in a single stage by a Ritter reaction. Depending on the reaction mixture, two types of Ritter reaction are thus distinguished: one with opening of the oxetane, resulting in a linear form of the chain which is directly and completely functionalized, the other resulting in the direct formation of an oxazoline. The xe2x80x9c*xe2x80x9d symbol indicates the presence of an asymmetric carbon, with an R or S configuration. In both cases, the Ritter reaction is stereospecific, with retention of C-2 configuration and inversion of C-3 configuration. The process according to the invention is advantageously carried out on one of the enantiomers of the cis-xcex2arylglycidate derivative of general formula I, so as to obtain the corresponding enantiomer of the linear chain or of the oxazoline, without subsequently requiring a racemic resolution. According to the method of preparation of the cis-xcex2-arylglycidate derivative of general formula I described below, R represents an optically pure enantiomer of a highly sterically hindered chiral hydrocarbon radical, advantageously a cycloalkyl substituted by one or more alkyl groups, in particular a cyclohexyl. R will then preferably be one of the enantiomers of the menthyl radical, in particular (+) menthyl.
1. Direct Synthesis of the Linear Chain
The direct synthesis of the linear chain by the Ritter reaction comprises reacting a cis-xcex2-arylglycidate derivative of general formula I defined above with a nitrile of formula
R2xe2x80x94CN
in which
R2 represents an aryl radical, preferably a phenyl,
in the presence of a proton acid, such as sulphuric acid, perchloric acid, tetrafluoroboric acid, and the like, and of water.
A xcex2-arylisoserine derivative of general formula IIa 
in which Ar, R and R2 are defined above, is then obtained.
The reaction is carried out with inversion of the configuration of the C-3 of the cis-xcex2-phenylglycidate derivative. Thus, starting from a (2R,3R)-cis-xcex2-phenylglycidate derivative, the corresponding xcex2-arylisoserine derivative of (2R,3S) configuration is obtained.
The Ritter reaction is carried out in an appropriate solvent, at a temperature ranging from xe2x88x9275 to +25xc2x0 C.
The appropriate solvent can be the nitrile itself, when it is liquid at the reaction temperature, or alternatively the acid itself (sulphuric, perchloric or tetrafluoroboric), or a solvent, such as, for example, methylene chloride or ethyl ether. The proton acids conventionally used can contain the water necessary for the hydrolysis.
When benzonitrile (R2=phenyl) is employed with the cis-xcex2-arylglycidate of general formula I of (2R,3R) configuration for which Ar represents a phenyl, then the corresponding xcex2-arylisoserine derivative of general formula IIa of (2R,3S) configuration for which Ar and R2 represent a phenyl is directly obtained, which product is none other than the precursor of the side chain of paclitaxel.
2. Direct Synthesis of the Cyclic Chain
In this method, a Ritter reaction is also carried out with a nitrile of formula
Rxe2x80x22xe2x80x94CN
in which Rxe2x80x22 represents R2 defined above or a lower alkyl or lower perhaloalkyl radical, such as trichloromethyl, in the presence of a Lewis acid, in particular the boron trifluoride acetic acid complex, boron trifluoride etherate, antimony pentachloride, tin tetrachloride, titanium tetrachloride, and the like, or of a proton acid, such as, for example, tetrafluoroboric acid, the reaction being carried out in anhydrous medium.
As for the synthesis of the linear chain, the solvent can be the nitrile itself, when it is liquid at the reaction temperature, or alternatively an appropriate solvent, such as, for example, methylene chloride or ethyl ether. The reaction temperature also ranges from xe2x88x9275 to +25xc2x0 C.
In the absence of water, an intramolecular Ritter reaction is carried out and the oxazoline of general formula IIb 
in which Ar, R and Rxe2x80x22 are as defined above, is obtained.
As in the Ritter reaction in the presence of water, the reaction is carried out with inversion of the configuration of the C-3 of the cis-xcex2-phenylglycidate derivative. Thus, starting from a (2R,3R)-cis-xcex2-phenylglycidate derivative, the corresponding oxazoline of (2R, 3S) configuration is obtained.
For both Ritter reactions, in order to avoid the formation of a free carbocation which is the cause of many potential side reactions, the reactants are preferably added in the following order: i) the complex between the nitrile and the acid is first formed, then ii) the acid catalyst is added to the mixture composed of the oxirane and the nitrile.
The products obtained by this first stage, which are xcex2-arylisoserine derivatives of general formula IIa or oxazoline derivatives of general formula IIb, can be further converted in a second optional stage described hereinbelow or then converted to acids by controlled saponification, before being coupled to a protected baccatin derivative for the hemisynthesis of taxanes, in particular of paclitaxel and its 10-deacetylated derivatives or of docetaxel. In the case of xcex2-arylisoserine derivatives of general formula IIa, the saponification can be preceded by a conventional stage of protection of the hydroxyl by an appropriate protective group. A derivative of general formula IIxe2x80x2a 
in which
Ar, R and R2 are defined above, and
GP represents a protective group for the hydroxyl functional group which is appropriate for the synthesis of taxanes, in particular chosen from alkoxy ether, aralkoxy ether, aryloxy ether or haloalkoxycarbonyl radicals, such as, for example, methoxymethyl, 1-ethoxyethyl, benzyloxymethyl or (xcex2-trimethylsilylethoxy)methyl groups, tetrahydropyranyl or xcex2-alkoxycarbonyl (TrOC) radicals, xcex2-halogenated or alkylsilyl ethers or alkoxyacetyl, aryloxyacetyl, haloacetyl or formyl radicals, is then obtained.
3. Conversion of the Derivatives of Formula IIa or IIb
The derivatives of general formula IIa or IIb obtained above can optionally be converted into novel intermediates which are side chain precursors in the hemisynthesis of taxanes. These conversions take place with retention of the configuration of the C-2 and C-3 positions. The novel intermediates obtained will thus have the same stereochemistry as the derivatives of formula IIa or IIb from which they derive. The products obtained in this second stage are subsequently converted into acids by controlled saponification, before being coupled with a protected baccatin derivative for the hemisynthesis of taxane, in particular of paclitaxel or of docetaxel.
3.1 Cyclization of the Derivatives of General Formula IIa
The derivatives of general formula IIa can subsequently be converted into oxazolines of formula IIb according to conventional methods of the state of the art (WO 94/14787).
The xcex2-arylisoserine derivatives of general formula IIa can also be converted into novel oxazolidinone cyclic intermediates of general formula IIIxe2x80x2a 
in which Ar and R are defined above and Rxe2x80x32 represents Rxe2x80x22 defined above, an alkoxy radical, preferably a t-butoxy radical, or a linear or branched alkyl radical comprising at least one unsaturation, for example a 1-methyl-1-propylene radical, and the corresponding dialkyl acetals.
The oxazolidinones of general formula IIIxe2x80x2a are obtained first of all by reacting a xcex2-arylisoserine derivative of general formula IIa with a haloalkoxycarbonyl ester, in particular 2,2,2-trichloroethoxycarbonyl (TrOC), and then by cyclization in the presence of a strong organic base, such as diazabicycloundecene (DBU). An oxazolidinone derivative of general formula IIIa 
in which Ar and R are defined above, is then obtained.
The derivatives of general formula IIIa can also be obtained by direct synthesis, by reacting the xcex2-arylglycidate derivatives of formula IIxe2x80x2a with urea.
The acylated derivatives of general formula IIIxe2x80x2a are obtained by introducing the Rxe2x80x32xe2x80x94COxe2x80x94 radical according to the usual acylation techniques, in the presence of an appropriate acylating agent, for example an acyl halide of formula Rxe2x80x32xe2x80x94COxe2x80x94X, in which Rxe2x80x32 is defined above and X represents a halogen, or an anhydride of the corresponding acid.
The dialkyl acetals are obtained according to the usual techniques for the formation of acetals.
3.2 Opening of the Oxazoline of General formula IIb
The xcex2-arylisoserine derivative of general formula IIIb 
in which Ar, R and Rxe2x80x22 are defined above, is obtained by hydrolysis of the oxazoline of general formula IIb in acidic medium.
Advantageously, when Rxe2x80x22 represents a lower perhaloalkyl, such as trichloromethyl, the Rxe2x80x22xe2x80x94COxe2x80x94 radical constitutes a protective group for the hydroxyl functional group.
This taxane side chain precursor can then be converted into amides of general formula IIIxe2x80x2b 
in which
Ar, R, Rxe2x80x22 and Rxe2x80x32 are defined above.
The precursor of the side chain of paclitaxel (Rxe2x80x32=phenyl) or of docetaxel (Rxe2x80x32=t-butoxy) can thus be obtained without distinction.
4. Preparation of the cis-xcex2-arylglycidic Acid Derivative of Formula I
The cis-xcex2-arylglycidic acid derivative of formula I can be prepared according to conventional processes of the state of the art or by simple esterification of cis-xcex2-arylglycidic acid with the corresponding alcohol Rxe2x80x94OH. In order to improve the overall yield in the synthesis of taxane chain precursors, a cis-xcex2-arylglycidate derivative of general formula I 
in which
Ar is defined above and
R represents an optically pure enantiomer of a highly sterically hindered chiral hydrocarbon radical,
is prepared in the process according to the invention by reacting the aldehyde of formula
Arxe2x80x94CHO
with the haloacetate of formula
Xxe2x80x94CH2xe2x80x94COOR
Ar and R being defined above and
X representing a halogen, in particular a chlorine or a bromine.
Advantageously, the optically pure enantiomer of a highly sterically hindered chiral hydrocarbon radical is a cycloalkyl substituted by one or more alkyl groups, in particular a cyclohexyl.
The method involves a Darzens"" reaction through which a mixture of the two diastereoisomers, ester of (2R,3R-cis-xcex2-arylglycidic acid and (2S,3S)-cis-xcex2-arylglycidic acid and of an optically pure enantiomer of the chiral alcohol Rxe2x80x94OH, is obtained, since the Darzens"" reaction, carried out with a highly sterically hindered haloacetate, results essentially in the cis form of the xcex2-arylglycidate. Advantageously, the highly sterically hindered chiral hydrocarbon radical will be chosen so that it allows the physical separation of the two diastereoisomers from the reaction mixture, for example by selective crystallization, without requiring a stereospecific separation of the desired enantiomer at the end of the reaction by conventional crystallization or chiral column chromatography methods.
Advantageously, Rxe2x80x94OH represents menthol, one of the rare highly sterically hindered chiral alcohols which is economic and commercially available in both its enantiomeric forms.
In the process for the synthesis of a precursor of the taxane side chain, the goal is to prepare a cis-xcex2-phenylglycidate of (2R,3R) configuration. In this case, the highly sterically hindered chiral hydrocarbon radical R will be selected so that the diastereoisomer of the cis-xcex2-phenylglycidate of (2R,3R) configuration crystallizes first from the reaction mixture. When Rxe2x80x94OH is menthol, (+)-menthol is advantageously employed.
The asymmetric Darzens"" reaction is carried out in the presence of a base, particularly an alkali metal alkoxide, such as potassium tert-butoxide, or an amide, such as lithium bistrimethylsilylamide, in an appropriate solvent, in particular an ether, such as ethyl ether, at a temperature ranging from xe2x88x9278xc2x0 C. to 25xc2x0 C. The reaction results in a diastereoisomeric mixture composed virtually exclusively of the cis-glycidates, which can reach a yield of greater than 95%, in the region of 97%. Treatment of the isolated product in an appropriate solvent, in particular a methanol/water mixture, makes it possible to readily obtain physical separation of the required diastereoisomers. By fractional crystallization (2 stages), rapid enrichment in the desired diastereoisomer is obtained, with a diastereoisomeric purity of greater than 99%.
The latter point is particularly important because it conditions the isomeric purity of the final taxane, the undesirable diastereoisomers exhibiting their own biological activity which is different from that of the desired taxane.
It is remarkable to observe that the selective use of the two enantiomers of the menthyl ester makes it possible to access, using the same process, the 2 precursor diastereoisomers of the two enantiomers of glycidic acid.
In addition to a fairly high yield of pure isolated diastereoisomer (up to 45%), the diastereoisomeric purity of the major product of the reaction, the ease of implementation of the reaction, the simplicity and the speed of the purification, and the low cost of the reactants and catalysts make the industrial synthesis of this key intermediate in the asymmetric synthesis of xcex2-amino acids easy and economical to access.
When a derivative of general formula I obtained by an asymmetric Darzens"" reaction is used in the process according to the invention, the derivatives of general formulae IIa, IIxe2x80x2a, IIb, IIIa, IIIb and IIIxe2x80x2b defined above are then obtained for which R represents an optically pure enantiomer of a highly sterically hindered chiral hydrocarbon radical, such as a cycloalkyl substituted by one or more alkyl groups, in particular a cyclohexyl, preferably menthyl, advantageously (+)-menthyl.
The present invention also relates to these derivatives, which are of use as intermediates in the synthesis of taxane side chains.
It should be noted that the present process constitutes a very rapid access to the substituted chiral oxazolines already described in the literature (WO 94/14787), in 3 stages from commercially available products, instead of 6 to 8 stages.
5. Controlled Saponification
A controlled saponification of the derivatives of general formulae IIa, IIxe2x80x2a, IIb, IIIa, IIIb and IIIxe2x80x2b is carried out under mild conditions, so as to release the acidic functional group while retaining the structure of the said derivatives, for example in the presence of an alkali metal carbonate in a methanol/water mixture.
After controlled saponification, the derivatives of general formulae IIa, IIxe2x80x2a, IIb, IIa, IIIb and IIIxe2x80x2b defined above in which R represents a hydrogen atom are obtained, which derivatives can be employed directly in the hemisynthesis of taxanes by coupling with an appropriate baccatin III derivative.
6. Hemisynthesis of Taxanes
6.1 Esterification
The present invention thus also relates to a process for the hemisynthesis of taxanes of general formula IV,
Cxe2x80x94Bxe2x80x83xe2x80x83(IV)
in which
C represents a side chain chosen from the radicals of following formulae: 
xe2x80x83in which Ar, R2, Rxe2x80x22, Rxe2x80x32, R3 and GP are defined above, and
B represents a radical derived from baccatin III of general formula V 
in which
Ac represents the acetyl radical,
Bz represents the benzoyl radical,
Me represents the methyl radical,
R4 represents an acetyl radical or a protective group for the hydroxyl functional group GP1, and
R5 represents a protective group for the hydroxyl functional group GP2, by esterification of an appropriate baccatin III derivative of general formula V, carrying a C-13 hydroxyl functional group, with one of the derivatives of general formulae IIa, IIxe2x80x2a, IIb, IIIa, IIIxe2x80x2a, IIIb and IIIxe2x80x2b defined above, in which R represents a hydrogen atom, under conventional conditions for the preparation of taxanes as defined in the state of the art (in particular: EP-0 253 738, EP-0 336 840, EP-0 336 841, EP-0 495 718, WO 92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169, WO 94/12482, EP-0 400 971, EP-0 428 376, WO 94/14787).
The GP1 and GP2 protective groups are, independently of one another, conventional groups employed in the hemisynthesis of taxanes, such as trialkylsilyls (EP-0 336 840) or TrOC (EP-0 336 841).
GP1 and GP2 also represent, independently of one another, linear or branched hindered haloalkoxycarbonyl radicals comprising at least one halogen atom. They are advantageously radicals in which the alkyl residue comprises between 1 and 4 carbon atoms and 3 or 4 halogen atoms, preferably chosen from 2,2,2-tribromoethoxycarbonyl, 2,2,2,1-tetrachloroethoxycarbonyl, 2,2,2-trichloro-t-butoxycarbonic and trichloromethoxycarbonyl radicals, radicals which are all more hindered than the haloalkoxycarbonyl (TrOC) used until now to protect taxanes in the 7 position.
GP1 and GP2 also represent, independently of one another, acyl radicals in which the carbon a to the carbonyl functional group carries at least one oxygen atom.
These acyl radicals are described in particular in EP-0 445 021. They are advantageously alkoxy- or aryloxyacetyl radicals of formula
R6xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94
in which R6 represents a sterically hindered alkyl radical, a cycloalkyl radical or an aryl radical, or arylidenedioxyacetyl radicals of formula 
in which Arxe2x80x3 represents an arylidene radical.
Sterically hindered alkyl is preferably understood to mean a linear or branched C1-C6 alkyl radical substituted by one or more bulky substituents chosen from halogens or linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy or C3-C6 cycloalkyl or aryl radicals. It will be, for example, a tert-butyl or triphenylmethyl radical.
Cycloalkyl is preferably understood to mean a C3-C6 cycloalkyl radical optionally substituted by one or more bulky substituents chosen from halogens or linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy or aryl radicals. Advantageously, it is a cyclohexyl radical substituted by one or more linear or branched C1-C6 alkyl radicals, such as, for example, menthyl, its racemate or its enantiomers and their mixtures in all proportions.
Aryl is preferably understood to mean a phenyl, naphthyl, anthryl or phenantryl radical optionally substituted by one or more bulky substituents chosen from halogens or linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy or aryl radicals, in particular the phenyl radical. It is preferably a phenyl radical optionally substituted by one or two above bulky substituents orths and ortho""- to the ether bond.
Finally, arylidene is preferably understood to mean a phenylene, naphthylene, anthrylene or phenanthrylene radical optionally substituted by one or more bulky substituents chosen from halogens or linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy or aryl radicals, in particular the phenyl radical.
GP1 and GP2 also represent, independently of one another, a trialkylgermanyl radical or together form a divalent radical of formula
xe2x80x94SiR7xe2x80x94Oxe2x80x94SiR8xe2x80x94
in which
R7 and R8, independently of one another, represent a sterically hindered alkyl radical as defined above; in particular, R7 and R8 each represent an isopropyl radical.
6.2 Optional Opening
When C represents a radical of formula IIb or IIIa, the oxazoline ring is opened in order to obtain a taxane derivative of formula VI 
in which
Ac, Bz, Me, Ar, Rxe2x80x22, R4 and R5 are defined above.
The IIb, IIIa and IIIxe2x80x2a radicals are generally opened by hydrolysis in acidic or basic medium. The radical of formula IIb can be opened according to the methods described in the state of the art (in particular WO 94/14787), by hydrolysis in acidic medium, followed by treatment in basic medium, in order to obtain the derivative of general formula VI.
6.3 Deprotection
Finally, the hydroxyls of the derivatives of general formula V or VI are deprotected by replacing the protective groups for the hydroxyl functional group, GP (when C represents the IIxe2x80x2a radical), GP1 (when R4 is other than an acetyl) and GP2, by a hydrogen atom according to the usual techniques.
For the derivatives of general formula V in which C represents a radical of formula IIb or IIIa and GP1 and/or GP2 are, independently of one another, conventional groups employed in the hemisynthesis of taxanes, such as trialkylsilyls, the deprotection is carried out simultaneously with the opening described above.
When GP1 and/or GP2 are bulky haloalkoxycarbonyl radicals, deprotection is carried out according to the usual techniques described for TrOC, by the action of zinc or of zinc doped with heavy metals, such as copper, in an organic solvent, in particular in acetic acid, tetrahydrofuran or ethyl alcohol, with or without water.
When GP1 and/or GP2 are acyl radicals in which the carbon a to the carbonyl functional group carries at least one oxygen atom, deprotection is carried out in basic medium by saponification in methanol at low temperature, advantageously with ammonia in methanol at a temperature of less than 10xc2x0 C., preferably in the region of 0xc2x0 C.
For the case where C represents a radical of formula IIb, opening of the oxazoline is carried out simultaneously with deprotection in basic medium, in order to result, in one stage, in the corresponding taxane derivative of general formula VI in which R4 represents an acetyl radical or a hydrogen atom and R5 represents a hydrogen atom, in contrast to the opening in acidic medium described in the state of the art, which requires a second stage in basic medium.
The known protective groups are removed using known methods and the oxazoline chain, when it was present, opened out by hydrolysis, giving taxanes in every respect identical to the reference taxanes. By way of example, without, however, limiting the scope of the invention, paclitaxel, 10-deacetyltaxol, cephalomanine and docetaxel can be obtained from the corresponding protected derivatives.
The deblocking of the acyls in which the carbon xcex1 to the carbonyl functional group carries at least one oxygen atom was first attempted under the conventional conditions regarded as the mildest, that is to say zinc acetate in methanolic medium at reflux. In this case, as the reaction was complete in a few hours (compared to a few days for acetates), the C-7 epimer resulting from the conventional retroaldolization equilibrium was always isolated, in addition to the desired product. It being presumed that, even under the neutral, indeed slightly acidic, conditions, the main agents responsible were methanol and especially the temperature, we returned to the standard conditions for deblocking acyls described by early writers, by saponification in basic medium in ethanol at low temperature. Under these conditions, no significant epimerization was observed. By way of example, we obtained paclitaxel, 10-deacetyltaxol, cephalomanine and docetaxel, in every respect identical to the reference taxanes, from the corresponding alkoxy- or aryloxyacetylated derivatives.
Finally, it should be noted that all the methods described above, which are nevertheless targeted at improving the overall yield of the hemisynthesis, consist in synthesizing the phenylisoserine chain beforehand, for the purpose of converting it into one of the cyclic structures mentioned above (xcex2-lactams, oxazolidines or oxazolines). Thus, paradoxically, the apparent better performances in the coupling of these cyclic structures only compensates for the fall in overall yield caused by the addition of ring creation stages to the synthetic sequence for the linear chain (i.e., a total of 9 stages). For the general process for the synthesis of taxanes according to the invention, a product such as paclitaxel is obtained in only 5 stages:
(1S,2R,5S)-(+)-menthyl (2R,3R)-3-phenylglycidate
(1S,2R,5S)-(+)-menthyl (4S,5R)-2,4-diphenyl-4,5-dihydroxazole-5-carboxylate
saponification
hemisynthesis (esterification)
opening and deprotection.
Finally, the present invention relates to the synthetic intermediates of general formulae IV, V and VI described above which are of use in the general synthesis of taxanes, a subject of the present invention.
Generally, hydroxycarbon radical is preferably understood to mean, according to the invention, a saturated or unsaturated hydrocarbon radical which can comprise one or more unsaturations, such as an optionally unsaturated linear or branched alkyl, an optionally unsaturated cycloalkyl, an aralkyl or an aryl, it being possible for each optionally to be substituted by one or more substituents, in particular alkyl substituents.
Linear or branched alkyl is preferably understood to mean, according to the invention, a C1-C6 alkyl, in particular chosen from the methyl radical, ethyl radical, propyl radical, isopropyl radical, butyl radical and its various branched isomers, such as, for example, tert-butyl, pentyl radical and hexyl radical and their various branched isomers. This definition also applies to the alkyl residues of the alkoxy or aralkoxy radicals.
Cycloalkyl is preferably understood to mean, according to the invention, a C3-C6 cycloalkyl, in particular chosen from the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals.
Aryl is preferably understood to mean, according to the invention, an aromatic or heteroaromatic radical, in particular chosen from the phenyl, naphthyl, anthryl, phenantryl, pyridyl or pyrimidyl radicals and the like.
Finally, halogen is preferably understood to mean chlorine, bromine or iodine. The haloalkoxycarbonyl radicals are preferably radicals in which the alkyl residue comprises between 1 and 4 carbon atoms and 3 or 4 halogen atoms.
The general process for the synthesis of taxanes according to the invention is repeated in Scheme 1 below, wherein R represents (+)-menthyl and R2 or Rxe2x80x22 represent phenyl.
The final stage in the hemisynthesis of taxanes by the process according to the invention is summarized in Schemes 2 and 3 below. Scheme 2 summarizes the synthesis of paclitaxel from derivatives of formula IV defined above in which C represents a radical of formulae IIb or IIIxe2x80x2a. Scheme 3 summarizes the synthesis of 10-deacetyltaxol from a derivative of formula IV in which C represents a radical of formula IIb.
Of course, the same synthetic schemes can be used for the other definitions of the substituents. 